P12.36.A ISOCITRATE DEHYDROGENASE INHIBITION PRIMES GLIOBLASTOMA CELLS FOR STATIN-INDUCED CELL DEATH

Abstract BACKGROUND Isocitrate dehydrogenases (IDH1/2) represent the most frequently mutated metabolic enzymes in human malignancies, with a particularly high prevalence in adult-type glioma. While recent advances in targeted therapies have brought these enzymes into the spotlight, the primary focus has been on their role in driving tumor progression. However, several studies have identified changes in lipid metabolism of IDH-mutated cancers, suggesting a potential therapeutic vulnerability. The extent to which these changes are driven by the oncometabolite or also by the suppression of wild-type activity remains unclear. In this project, we aim to elucidate whether inhibition of wild-type enzyme could produce a metabolic vulnerability in IDH non-mutated glioblastoma. MATERIAL AND METHODS Effects of mono and combination therapy of multiple IDH inhibitors and diverse metabolic inhibitors on cell viability and clonogenicity were tested in the patient-derived IDH-wild type GBM model BTL1528 and cell line T98G. The therapeutic mechanisms were further explored by Western blot, Seahorse assay, and RNA expression array. The most effective combination was subsequently evaluated using MTT across a panel of patient-derived and commercial cell models. Additionally, changes in spheroid formation and viability were assessed. RESULTS Monotherapy with the IDH-mutant inhibitors demonstrated limited effects on cell viability but synergistic cytotoxicity when combined with mevalonate pathway-inhibiting statins. The most potent combinatorial effects were observed with the IDH2-mutant inhibitor enasidenib. This finding could be replicated in multiple cell models. Remarkably, the combination even increased the susceptibility of T98G, which is highly insensitive to both IDH inhibitors and statins. Pathway-level analysis of transcriptomic changes revealed suppression of the cholesterol biosynthesis pathway upon combination treatment. Intriguingly, data from the cell model BTL1528 indicate that primarily enasidenib drives these metabolic changes. Monotherapy with enasidenib induced downregulation of cholesterol biosynthesis, concurrent with PPARγ-mediated upregulation of cholesterol efflux mechanisms. CONCLUSION The combined use of IDH inhibitors and statins demonstrates highly synergistic cytotoxic effects in glioblastoma cell models. Our data suggest that reprogramming of the cholesterol metabolism by enasidenib sensitizes cells to statin-induced cell death. Further studies will investigate changes in metabolism more in-depth through metabolomics profiling. The in vivo efficacy will be assessed in xenograft mouse models. Through the repurposing of widely approved pharmacotherapies, these findings might be more readily translated into the clinics.